Evidence map›Paper›PMID 41427010›Full record

ArticleCell reports. Physical science2025

Understanding varenicline function via key receptor and ligand interactions.

Sheenagh G Aiken, Daniele Fiorito, Matthew Harper, Grzegorz Pikus, Juno Underhill, Jacob Murray, Joshua Rawlinson, AnnMarie C O'Donoghue, Cecilia Gotti, Sarah C R Lummis and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports. Physical science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Sheenagh G AikenSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Daniele FioritoSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Matthew HarperSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Grzegorz PikusSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Juno UnderhillSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
Jacob MurrayDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
Joshua RawlinsonDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
AnnMarie C O'DonoghueDepartment of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
Cecilia GottiCNR, Institute of Neuroscience, University of Milan, 20129 Milan, Italy.
Sarah C R LummisDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Teresa Minguez ViñasDepartment of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Franco ViscarraDepartment of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Isabel BermudezDepartment of Biological and Medical Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Timothy GallagherSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
A Sofia F OliveiraSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Approved by the US Food and Drug Administration in 2006, varenicline was the first nicotinic-based therapy for smoking cessation, targeting the α4β2 nicotinic acetylcholine receptor (nAChR). While inspired by cytisine, varenicline has distinct effects at both target and off-target receptors; however, despite being widely used clinically, the precise molecular interactions underpinning varenicline's mode of action remain unclear. Using a multidisciplinary approach, the interactions that set varenicline apart from related compounds such as nicotine and cytisine have been identified. In particular, the binding-site residues α4T139, α4T183, and especially β2S133 were shown to be key modulators for varenicline's function. Substituting β2S133 with valine significantly reduced efficacy, pinpointing it as a crucial determinant. Additionally, a set of novel varenicline variants showed that the positioning of the quinoxaline moiety in varenicline is essential for receptor activation. These insights reveal a unique interaction network at α4β2 that underlies varenicline's function, offering a deeper understanding of the ligand's working mechanism.

Indexed as

binding profilefunctional mutationsfunctional profileligand functionligand selectivitymolecular dynamics simulationsnicotinic acetylcholine receptorreceptor-agonist interactionsserotonin 5-HT receptor

Identifiers

PMID41427010
PMCPMC12711630

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.